The immature immune system renders newborns vulnerable to infections and meanwhile unable to mount a rapid protective immunity after vaccination. Currently, 4 million newborns under the age of 6 months die of vaccine-preventable diseases each year worldwide and the annual cost to treat infected newborns and infants reaches $690 million in USA alone. Enhancing newborn vaccine immunogenicity is the key to reduce early infection-associated high morbidity and mortality in newborns. A laser-based powder delivery (LPD) in combination with a clinical monophosphoryl lipid A (MPL) adjuvant (MPL/LPD) is proposed for improved newborn immunization. Laser generates self-renewable microchannels in the skin surface. After topical application of powder vaccine/MPL-coated array patches, vaccine/MPL can be efficiently deposited into these microchannels, dissolved in situ, and efficiently taken up by or activate skin antigen-presenting cells (APCs). MPL/LPD-based immunization is expected to profoundly improve newborn vaccine immunogenicity because LPD delivers vaccines to APC-rich skin tissue; laser recruits a large number of APCs around each microchannel for more efficient antigen uptake; MPL further enhances vaccine-induced immune response by stimulation of maturation of resident and recruited APCs. Surrounded by normal healthy skin, these temporarily opened microchannels can be resealed and replaced with newly synthesized tissue within 24 hours to ensure the safety of this technology. LPD/MPL-based immunization also eliminates needle injection and causes no pain because laser only affects the epidermal tissue. Besides the significantly improved vaccine immunogenicity and the superior safety, the needle-free, painless MPL/LPD-based immunization is promising to overcome interference of maternal antibodies by delivery of powder vaccines to separated microchannels for gradual dissolution and efficient uptake inside the skin. The compartmentalized vaccine delivery and antigen uptake pattern is expected to greatly reduce systemic distribution and inactivation of vaccines by circulating antibodies. Polysaccharide-encapsulated bacteria, such as Haemophilus influenzae type b (Hib), are leading causes of serious infections in infants. Thus, Hib vaccine will be used to explore MPL/LPD-based immunization in newborn mice (specific aim 1) and pigs (specific aim 2). MPL/LPD prime/boost immunization will be compared with 4 intramuscular immunizations in the presence of Alum adjuvant to induce a protective antibody response in the presence or absence of maternal antibodies in this proposal. This application responds to Challenges in infant immunity workshop organized by NIAID in 2010 by presenting a novel laser-based delivery and adjuvantation technology for improved newborn immunization. The novel immunization strategy will have a broad impact on delivery and adjuvantation of not only Hib vaccine but also other vaccines with a low immunogenicity in the clinic.